VHL – Renal Cell Carcinoma

Germline mutations in the VHL tumor suppressor gene confer autosomal dominant predisposition to renal cell carcinoma (Renal Cell Carcinoma). Families with hereditary von Hippel–Lindau syndrome demonstrate segregation of VHL mutations with RCC, with at least 5 additional affected relatives reported per kindred and 22 kindreds described (PMID:7977367). A representative pathogenic variant is c.263G>T (p.Trp88Leu) reported in a metastatic clear cell RCC case (PMID:29118224).

Somatic VHL inactivation is one of the most frequent events in sporadic clear cell RCC. In 39 clear cell RCCs, 22 (56%) harbored somatic VHL mutations including 15 deletions, 3 insertions, 3 missense and 1 nonsense alteration (PMID:8187067). In a Dutch cohort of 187 clear cell RCCs, 114 (61%) carried VHL alterations, primarily truncating mutations (47%) and promoter hypermethylation (35%) (PMID:15932632). These studies define a broad variant spectrum—missense, nonsense, frameshift, splice and epigenetic changes—driving biallelic VHL loss.

The pathogenic mechanism is loss of pVHL E3 ubiquitin ligase function, preventing hydroxylated HIF1α degradation. Wild-type pVHL binds and inhibits PKCζ/δ, blocking MAPK-mediated VEGF overexpression (PMID:9346879). Reconstituted VHL complexes ubiquitinate HIF1α in vitro (PMID:10973499), and VHL–elongin BC assembly requires TRiC-mediated folding (PMID:10635329). Conditional Vhl knockout mice develop hepatic hemangiomas, multiorgan angiectasis and impaired spermatogenesis mirroring human VHL syndrome (PMID:14500363).

Conflicting evidence is minimal. A rare germline P25L variant in exon I has allele frequency ∼0.5% in controls and does not impair pVHL function, underscoring the need to distinguish benign polymorphisms (PMID:11257211).

Integration of genetic and experimental data yields a Definitive classification. Germline and somatic VHL mutations consistently co-segregate with RCC, and multiple functional assays confirm haploinsufficiency and loss-of-function mechanisms. Additional evidence from deep-intronic and founder alleles exceeds current scoring but aligns with known biology.

Key Take-home: VHL mutation status is essential for RCC diagnosis, risk stratification and targeted anti-angiogenic therapy.

References

• Cancer research • 1994 • Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas PMID:8187067
• BMC cancer • 2005 • Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study PMID:15932632
• The Journal of Biological Chemistry • 1997 • The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways PMID:9346879
• Cancer research • 2003 • Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene PMID:14500363
• Molecular cell • 1999 • Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC PMID:10635329
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex PMID:10973499
• Journal of the National Comprehensive Cancer Network : JNCCN • 2017 • Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation PMID:29118224

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